The receptor for the monocyte-macrophage specific growth factor, CSF-l (c-fms) and its viral homologue, v-fms, are transmembrane glycoproteins that exhibit tyrosine kinase activity. We have been attempting to identify the significant differences between v-fms and c-fms that contribute to the transforming properties of the viral gene. We previously reported studies on a number of v- fms/human c-fms hybrid genes in which we found that the c-fms carboxyl terminal sequences appear to act in the negative regulation of the receptor. To more fully study the differences between v-fms and c-fms, we have cloned a full length mouse c-fms cDNA and are introducing specific amino acid substitutions with the aim of examining the effect of these changes in vivo. We have also constructed a chimeric receptor between the human epidermal growth factor (EGF) receptor ligand binding and transmembrane domains and the human c-fms cytoplasmic region including the tyrosine kinase domain and the carboxyl terminus. Since hematopoietic cells do not express the receptor for EGF, the chimeric receptor can be introduced into these cells and the cellular response to EGF can be examined. In addition, it may be possible to provide an inducible growth advantage to cells that express this chimera. To date, this gene has been introduced into both NIH 3T3 and IL-3 dependant 32D cells. It has been found to be expressed on the cell surface and to be of the expected size. Further, this receptor exhibits autophosphorylation that can be further stimulated by the addition of EGF. The cells bearing the chimeric receptor, however, do not exhibit a mitogenetic response upon addition of EGF. The reason for this block is unknown and will be the subject of further investigation.